Expressed cytochromes P450 can be used as activation systems for promutagens and to screen natural compounds for isozyme specific inhibitors. In order to optimize the activities of cDNA-expressed mouse CYP1A1, mouse CYP1A2, human CYP1A2, and human CYP2B6, in Hep G2 and TK- cells, these P450s were co-expressed with human NADPH-oxidoreductase. In hepatoma cells, co-expression resulted in a greater affinity of the enzyme to its substrate or inhibitor. With embryoblast cells, co- expression resulted in an increase in specific activity of CYP1A enzymes without a change in their affinity values. The modulatory effects of several natural flavonoids were studied for their effects on cDNA- expressed mouse and human CYP1A isozymes. A comparison of the mouse and human CYP1A2s revealed a species specific difference in their responses to flavonoids. Structure-activity relationships showed the importance of hydroxyl groups in the 5- and 7-positions of the A ring of the flavone nucleus. The ortho-orientation of a hydroxyl group on the B ring was of importance too. In addition, the recombinant P450s were used to seek among natural and synthetic compounds for isozyme specific monooxygenase inhibitors.